Poly(ester-amide) and poly(amide) coatings for implantable medical devices for controlled release of a protein or peptide and a hydrophobic drug

• US 8,323,676 B2
• Filed: 06/30/2008
• Issued: 12/04/2012
• Est. Priority Date: 06/30/2008
• Status: Active Grant

• Current Assignee: Abbott Cardiovascular Systems Incorporated (Abbott Laboratories Incorporated)
• Original Assignee: Abbott Cardiovascular Systems Incorporated (Abbott Laboratories Incorporated)
• Inventors: Lim, Florencia, Trollsas, Mikael O., Xu, Xinmin, Maslanka, Bozena Zofia
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): AL-AWADI, DANAH J
• Application Number:
  US12/165,521
• Publication Number:
  US 20090324672A1
• Time in Patent Office: 1,618 Days
• Field of Search: None
• US Class Current: 424/423
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C08L 77/00 Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain of polyhydrazides C08L79/06; of polyamideimides or polyamide acids C08L79/08; Compositions of derivatives of such polymers

Abstract

This invention is generally related to coatings for implantable medical devices, such as drug delivery vascular stents. The coating includes a drug reservoir layer above the outer surface of the device body, the drug reservoir layer with a peptide or protein, a hydrophobic drug, and a polymer with a weight average molecular weight between about 10,000 to about 150,000 Daltons. A preferred polymer is a poly(ester amide) polymer.

Claims

1. An implantable medical device comprising:

a device body and a coating disposed over the device body, the coating comprising;

a drug reservoir layer comprising;

a peptide or protein;

a hydrophobic drug; and

a polymer with a weight average molecular weight between about 10 to about 150 K Daltons;

wherein the mass ratio of the peptide or protein to the hydrophobic drug is from about 1;

0.1 to about 1;

10;

wherein the mass ratio of the protein or peptide to the polymer is from about 1;

0.1 to about 1;

10;

wherein the cumulative release of the peptide or protein from the drug reservoir layer is between about 5% and about 50% at 24 hours and between about 10% and about 95% at 7 days; and

wherein the polymer is a poly(ester-amide) or a poly(amide) that is of the following formula;

2. The device of claim 1, wherein the implantable medical device is a stent.

3. The device of claim 1, wherein the cumulative release of the hydrophobic drug from the drug reservoir layer is between about 5% and about 50% at 24 hours and between about 10% and about 95% at 7 days.

4. The device of claim 1, wherein the cumulative release of the hydrophobic drug from the drug reservoir layer is between about 10% and about 35% at 24 hours and between about 25% and about 75% at 7 days.

5. The device of claim 1, wherein the mass ratio of the peptide or protein to the hydrophobic drug is from about 1:

0.2 to 1;

5.

6. The device of claim 1, wherein the mass ratio of the peptide or protein to the hydrophobic drug is from about 1:

0.5 to 1;

3.

7. The device of claim 1, wherein the mass ratio of the protein or peptide to the polymer is from about 1:

0.2 to about 1;

5.

8. The device of claim 1, wherein the mass ratio of the protein or peptide to the polymer is from about 1:

2 to about 1;

4.

13. The device of claim 1, wherein the hydrophobic drug is selected from the group consisting of sirolimus (rapamycin), biolimus A9, deforolimus, AP23572 (Ariad Pharmaceuticals), tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40- O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxypropyl)rapamycin, 40-O- [2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 40-O-tetrazolylrapamycin, 40-epi-(N1-tetrazole)-rapamycin, paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), dexamethasone, γ

-hiridun, clobetasol, dexamethasone acetate, mometasone, imatinib mesylate, midostaurin, feno fibrate, feno fibric acid, and prodrugs thereof, co-drugs thereof, and combinations thereof.

14. The device of claim 13, wherein the hydrophobic drug is everolimus.

15. The device of claim 13, wherein the hydrophobic drug is zotarolimus.

16. The device of claim 1, wherein the hydrophobic drug is an anti-proliferative.

17. The device of claim 1, wherein the peptide or protein is selected from the group consisting of cRGD, other similar size peptides and combinations thereof.

18. The device of claim 1, wherein the peptide or protein is selected from the group consisting of RGD, an RGD peptide, a cyclic RGD peptide (cRGD), a synthetic cyclic RGD (cRGD) mimetic, or a synthetic RGD mimetic and combinations thereof

19. The device of claim 18, wherein the peptide or protein is cRGD.

20. The device of claim 1, wherein the drug reservoir layer is between about 0.5 and about 9 μ

m in thickness.

21. The device of claim 1, wherein the mass ratio of (protein or peptide):

hydrophobic drug;

polymer is about 1;

1;

3.

9. An implantable medical device comprising:

a device body and a coating disposed over the device body, the coating comprising;

a drug reservoir layer comprising;

a peptide or protein;

a hydrophobic drug; and

a polymer with a weight average molecular weight between about 10 to about 150 K Daltons;

wherein the mass ratio of the peptide or protein to the hydrophobic drug is from about 1;

0.1 to about 1;

10;

wherein the mass ratio of the protein or peptide to the polymer is from about 1;

0.1 to about 1;

10;

wherein the cumulative release of the peptide or protein from the drug reservoir layer is between about 5% and about 50% at 24 hours and between about 10% and about 95% at 7 days;

and

wherein the polymer is a poly(ester-amide) or a poly(amide) that is of the following formula;

10. The device of claim 9, wherein for the polymer

R_a1 is —

(CH₂)₈—

;

R_b1 R_b1′

R_b2 and R_b2′

the same and are —

(CH₂)—

(CH(CH₃)₂) ;

R_c1 is —

(CH₂)₆—

;

R_c2 is

11. The device of claim 9, wherein the peptide or protein is cRGD, and the hydrophobic drug is everolimus.

12. The device of claim 11, wherein the mass ratio of (protein or peptide):

hydrophobic drug;

polymer is about 1;

1;

3.

29. The device of claim 9, wherein R_c2 is selected from the group consisting of

30. The device of claim 9, wherein the hydrophobic drug is selected from the group consisting of sirolimus (rapamycin), biolimus A9, deforolimus, AP23572 (Ariad Pharmaceuticals), tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40- O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxypropyl)rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 40-O-tetrazolylrapamycin, 40-epi-(N1-tetrazole)-rapamycin, paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), dexamethasone, γ

-hiridun, clobetasol, dexamethasone acetate, mometasone, imatinib mesylate, midostaurin, feno fibrate, feno fibric acid, and prodrugs thereof, co-drugs thereof, and combinations thereof;

and

the peptide or protein is selected from the group consisting of RGD, an RGD peptide, a cyclic RGD peptide (cRGD), a synthetic cyclic RGD (cRGD) mimetic, a synthetic RGD mimetic, other similar size peptides, and combinations thereof.

22. An implantable medical device comprising:

a device body and a coating disposed over the device body, the coating comprising;

a drug reservoir layer comprising;

a peptide or protein;

a hydrophobic drug;

a polymer with a weight average molecular weight between about 10 to about 150 K Daltons;

wherein the mass ratio of the peptide or protein to the hydrophobic drug is about 1;

0.1 to about 1;

10;

wherein the ratio of the sum of the mass of peptide or protein and the mass of the hydrophobic drug to the mass of the polymer is about 1;

1 to about 1;

12;

wherein the drug reservoir layer thickness is between about 0.5 and about 7 μ

m in thickness; and

wherein the polymer is poly(ester-amide) that is a random copolymer having the formula;

23. The device of claim 22, wherein the hydrophobic drug is selected from the group consisting of sirolimus (rapamycin), biolimus A9, deforolimus, AP23572 (Ariad Pharmaceuticals), tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxypropyl)rapamycin, 40-O-[2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 40-O-tetrazolylrapamycin, 40-epi-(N1-tetrazole)-rapamycin, paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), dexamethasone, γ

-hiridun, clobetasol, dexamethasone acetate, mometasone, imatinib mesylate, midostaurin, feno fibrate, feno fibric acid, and prodrugs thereof, co-drugs thereof, and combinations thereof.

24. The device of claim 22, wherein the peptide or protein is selected from the group consisting of RGD, an RGD peptide, a cyclic RGD peptide (cRGD), a synthetic cyclic RGD (cRGD) mimetic, a synthetic RGD mimetic, other similar size peptides, and combinations thereof.

26. The method of claim 23, wherein the cumulative release of the hydrophobic drug from the drug reservoir layer is between about 5% and about 50% at 24 hours and between about 10% and about 95% at 7 days.

27. The method of claim 23, wherein the cumulative release of the hydrophobic drug from the drug reservoir layer is between 10% and about 35% at 24 hours and between about 25% and about 75% at 7 days.

25. A method of fabricating a coated implantable medical device comprising:

providing an implantable medical device;

providing a peptide or protein, a hydrophobic drug, and a polymer with a weight average molecular weight between about 10,000 to about 150,000 Daltons;

dissolving or dispersing the peptide or protein, the hydrophobic drug, and the polymer in ethanol wherein the mass ratio of the peptide or protein to the hydrophobic drug is from about 1;

0.1 to about 1;

10; and

wherein the mass ratio of the protein or peptide to the polymer is from about 1;

0.1 to about 1;

10;

applying the ethanol solution/dispersion to the implantable medical device; and

removing the ethanol to form a drug reservoir layer;

wherein the cumulative release of the peptide or protein from the drug reservoir layer is between about 5% and about 50% at 24 hours and between about 10% and about 95% at 7 days; and

wherein the polymer is a poly(ester-amide) or a poly(amide) that is of the following formula;

28. A coated implantable medical device fabricated by the method of claim 25.

31. A method of fabricating a coated implantable medical device comprising:

providing an implantable medical device;

providing a peptide or protein, a hydrophobic drug, and a polymer with a weight average molecular weight between about 10,000 to about 150,000 Daltons;

dissolving or dispersing the peptide or protein, the hydrophobic drug, and the polymer in ethanol wherein the mass ratio of the peptide or protein to the hydrophobic drug is from about 1;

0.1 to about 1;

10; and

wherein the mass ratio of the protein or peptide to the polymer is from about 1;

0.1 to about 1;

10;

applying the ethanol solution/dispersion to the implantable medical device; and

removing the ethanol to form a drug reservoir layer;

wherein the cumulative release of the peptide or protein from the drug reservoir layer is between about 5% and about 50% at 24 hours and between about 10% and about 95% at 7 days;

and

wherein the polymer is a poly(ester-amide) or a poly(amide) that is of the following formula;

32. A coated implantable medical device fabricated by the method of claim 31.